This application or an HIV Prevention Trial Unit (HPTU) describes the relevant experience, the exceptional research infrastructure, the access to high risk drug using populations, and the scientific depth of HIV prevention research at the University of Pennsylvania site. The work proposed here is responsive to the RFA and it is sharply focused on those segments of the population at highest risk of HIV infection. Although our site will initially focus exclusively on domestic populations, we believe the findings of these studies will also inform prevention sciences internationally and support expanded prevention trials in other countries. Building upon our successful involvement as a HIVNET site and with the addition of several key investigators, this application proposes work in three of the PTN scientific areas: l) microbicides; 2) behavioral interventions, and 3) substance related transmission. Specifically we propose to: * Conduct three Phase I microbicide studies with 30 subjects each * Participate in a Phase IIb study of a women's behavioral intervention with 500 high risk drug using women * Conduct a Phase I study of the behavior change among high risk IDUs The research agenda described in this application represents an extension of our current research activities. Proposed investigators are currently implementing several HIVNET funded protocols including a Phase II vaccine trial, a Phase I microbicide trial, and a feasibility study of a behavioral intervention for women. Additionally, these investigators are conducting HIV prevention research with support from NIDA, NIMH, and the CDC. These activities include a longitudinal study of injection drug users investigating the role of syringe exchange as a bridge to substance abuse treatment (NIDA); a study of the behavioral impact of a community based intervention targeting African American mothers and their adolescent sons (NIMH); and a Phase IV study of a school-based behavioral intervention involving 11,000 adolescents (CDC). This application will also bring together investigators able to contribute to the future scientific agenda of the PTN. Penn PTU investigators have extensive expertise in the areas of substance abuse treatment, women's behavioral interventions, behavioral interventions with adolescents, microbicide research, health policy, and evaluation design. Thus, an additional aim of our group is to be active participants in three of the PTN science working groups-Microbicides, Behavioral Intervention, and Substance Related Transmission.